CN1029400C - Preparation method of side chain vitamin D derivatives - Google Patents

Abstract

The invention relates to a novel side chain homologous vitamin D derivative shown in a general formula I, a preparation method thereof, a medicinal preparation containing the compound and application of the compound in pharmacy.

In the formula, R¹、R²、R³、R⁴、R⁵And R⁶Having the meaning as described in the specification; b and D are either each a hydrogen atom or together a second bond (E-configuration double bond); furthermore, either A is a direct bond between carbon atoms 20 and 22 and X is an alkyleneoxy- (CH)₂)_nO-, wherein n is 1-3, or A is a methylene group (-CH) between carbon atoms 20 and 22₂-) while X is an alkylene group- (CH)₂)_nOr an alkyleneoxy- (CH)₂)_nO-, wherein n-1-3. The novel compounds have the effect of preventing proliferation and differentiation of cells.

Description

The present invention relates to a side chain homologous vitamin D derivative represented by formula I, its preparation method, a pharmaceutical preparation containing the compound and its application in medicine.

In the formula, ^R represents a hydrogen atom, a hydroxyl group, or an acyloxy group containing 1 to 9 carbon atoms,

^R2 represents a hydrogen atom or an acyl group containing 1 to 9 carbon atoms, ^R3 or ^R4 represents a hydroxyl group or an acyloxy group containing 1 to 9 carbon atoms, and the other substituent represents a hydrogen atom, or ^R3 and ^R4 together represent an oxygen atom,

R ⁵ and R ⁶ each represent a linear or branched alkyl group containing up to 4 carbon atoms, a trifluoromethyl group, or together represent a saturated, unsaturated or aromatic group formed with a tertiary carbon atom. 3, 4, 5 or 6-membered carbocyclic rings or 3, 4, 5 or 6-membered heterocyclic rings containing 1 or 2 N atoms, O atoms or sulfur atoms,

B and D either each represent a hydrogen atom, or together represent a second bond (double bond in E configuration), and either

A represents a direct bond between carbon atoms 20 and 22, and

X represents an alkyleneoxy-(CH ₂ ) _n O- where n=1 to 3, or

A represents endomethylene-( _CH2- ) between carbon atoms 20 and 22, and

X represents an alkylene-(CH ₂ ) _n - or an alkyleneoxy-(CH ₂ ) _n O- where n=1 to 3, or

When A represents a direct bond and B and D together represent a secondary bond,

For the radicals R ¹ , R ² and possible acyloxy or acyl radicals in the radicals R ³ or R ⁴ are obtained especially from saturated carboxylic acids or from benzoic acid.

Cyclopropane or cyclohexyl rings are especially contemplated if R ⁵ and R ⁶ together form a saturated cyclic carbocycle with a tertiary carbon atom. As alkyl groups for ^R5 and ^R6 , especially those having 1 to 5 carbon atoms come into consideration.

According to the present invention, it is preferred that in general formula I, R ¹ , R ³ and R ⁴ represent a hydroxyl group or

R ⁵ and R ⁶ represent a methyl group or together with a tertiary carbon atom represent a cyclopropyl ring,

R ² represents a hydrogen atom and n is 1 or 2 side chain homologous vitamin D derivatives.

Preferably there is a double bond between carbon atoms 22 and 23 (when A is a direct bond) or between carbon atoms 23 and 24 (when A is a methyl group). Especially preferred compounds are:

24-(1(R)-Hydroxy-4-methylpentyl)-9,10-sanchole-5Z,7E,10(19),23E-tetraene-1(S),3(R)-di alcohol;

24-(1(S)-Hydroxy-4-methylpentyl)-9,10-sanchole-5Z,7E,10(19),23E-tetraene-1(S),3(R)-di alcohol;

24-(1(R)-Hydroxy-3-methylbutyl)-9,10-sanchole-5Z,7E,10(19),23E-tetraene-1(S),3(R)-di alcohol.

24-(1(S)-Hydroxy-3-methylbutyl)-9,10-sanchole-5Z,7E,10(19),23E-tetraene-1(S),3(R)-di alcohol.

24-(1(R)-Hydroxy-3-methylbutyl)-9,10-sanchole-5Z,7E,10(19)-triene-1(S),3(R)-diol.

24-(1(S)-Hydroxy-3-methylbutyl)-9,10-sanchole-5Z,7E,10(19)-triene-1(S),3(R)-diol.

24-(1(R)-Hydroxy-3-isopropoxypropyl)-9,10-sanchole-5Z,7E,10(19),23E-tetraene-1(S),3(R) -diol.

24-(1(S)-Hydroxy-3-isopropoxypropyl)-9,10-Sanchole-5Z,7E,10(19),23E-Tetraene-1(S),3(R) -diol.

24-Isopropoxymethyl-9,10-sanchole-5Z,7E,10(19),22E-tetraen-1(S),3(R),24(R)-triol.

24-Isopropoxymethyl-9,10-sanchol-5Z,7E,10(19),22E-tetraen-1(S),3(R),24(S)-triol.

24-(2-Isopropoxyethyl)-9, 10-sanchole-5Z, 7E, 10(19), 22E-tetraene-1(S), 3(R), 24(R)-tri alcohol.

24-(2-Isopropoxyethyl)-9, 10-sanchole-5Z, 7E, 10(19), 22E-tetraene-1(S), 3(R), 24(S)-tri alcohol.

26, 27-cyclo-24a, 24b-bisadditional carbon-9, 10-secocholesta-5Z, 7E, 10(19), 23E-tetraene-1(S), 3(R), 24a(R) - triols,

26, 27-cyclo-24a, 24b-bisadditional carbon-9, 10-secocholesta-5Z, 7E, 10(19), 23E-tetraene-1(S), 3(R), 24a(S) - Triols.

Natural vitamins D ₂ and D ₃ (see general formula V) themselves have no biological activity, and are only converted into biologically active metabolites after being hydroxylated at the 25-position in the liver or at the 1-position in the kidney . The role of vitamins D ₂ and D ₃ is to stabilize plasma-Ca ⁺⁺ and plasma-phosphate levels; they resist the decline in plasma-Ca ⁺⁺ levels.

Ergocalciferol: R ^a = R ^b = H, R ^c = CH ₃ , vitamin D ₂

Double bond C-22/23

Cholecalciferol: R ^a =R ^b =R ^c =H Vitamin D ₃

25-Hydroxycholecalciferol: R ^a = R ^c = H, R ^b = OH

1α-hydroxycholecalciferol: R ^a = OH, R ^b = R ^c = H

^1α ,-25-dihydroxycholecalciferol: Ra = ^Rb = OH,

R ^c = H calcitriol

In addition to their significant calcium and phosphate metabolism, vitamin D ₂ , D ₃ and their synthetic derivatives also have the effect of hindering proliferation and differentiation of cells (HF De Luca, Metabolism of Vitamin D in Steroid Hormone Biochemistry and Function, Hrsg.HLJMakin, 2nd ed., Blackwell Scientific Publishers, 1984 pp. 71-116). Overdosage (hypercalcemia) can occur when vitamin D is used.

1α-cholecalciferol hydroxylated at the 24-position, as reported by DE-AS 2526981, is much less toxic than the corresponding unhydroxylated 1α-cholecalciferol. These hydroxylated compounds are selectively active on calcium absorption in the intestine and are less potent in bone absorption than 1α-cholecalciferol.

The 24-hydroxyvitamin D analogues described in International Patent Application WO 87/00834 are useful in the treatment of various disorders in humans and animals caused by abnormal cell proliferation and/or cell differentiation. As for the different 1,25-dihydroxy-isovitamin D derivatives, De Luca mentioned not long ago that bone resorption and HL-60 cell differentiation were a variation in the various properties. Therefore, bone resorption in vitro is a direct measure of calcium activity in vivo. It has now been found that the side chain homologous vitamin D derivatives of the present invention represented by the general formula I unexpectedly have a more favorable spectrum of action than the vitamin D derivative calciferol (1α,25-dihydroxycholecalciferol). The effects on calcium and phosphate metabolism are markedly attenuated (reduced side effects due to overdose or necessary high doses), while proliferation arrest and cell differentiation are largely maintained (variation).

The vitamin D activity of the compounds of the invention was determined using the calcitriol receptor assay. The test was carried out using a specific receptor protein derived from the intestines of rickets chickens. Receptor-containing binding proteins were incubated with ³ H-calcitriol (0.5 ng/ml) in a reaction volume of 0.575 ml in the absence and presence of analytes for 1 hour in test tubes. To separate free and receptor-bound calcitriol, charcoal-dextran absorption was performed. For this, 200 μl of the charcoal-dextran suspension were added to each tube and incubated at 22° C. for 30 minutes. Next, the sample was centrifuged at 1500Xg for 10 minutes at 4°C. The supernatant was decanted and measured with a β-counter after equilibrating in Atom-Light for about 1 hour. Under the constant concentration of the reference substance ( ³ H-calcitriol), the competition curves obtained with different concentrations of the test substance and the reference substance (unlabeled calcitriol) were correspondingly connected, and the competition factor (KF) was calculated. The factor is defined as the concentration quotient of each test and reference substance necessary for 50% competition:

KF = (concentration of test substance at 50% competition)/(concentration of reference substance at 50% competition)

According to this, 24-(1-hydroxy-3-methylbutyl)-9,10-sanchole-5Z, 7E, 10(19), 23E-tetraene-1(S), 3(R)-di Alcohol (compound A) has a KF value of 2.0, while 24-(1-hydroxy-3-methylbutyl)-9,10-sequence-5Z, 7E, 10(19), 23E-tetraene-1 ( S), 3(S)-diol (Compound B) has a KF value of 3.6.

In order to determine the anti-proliferation ability of the compounds of the present invention, the following tests were carried out with compounds A and B as test substances.

With a modification of the method of Yuspa, S. and Harris, CC ("Altered differentiation of mouse epidermal cells after treatment with retinyl acetate in vitro", Exp. Cell Res. 86, pp. 95-105, 1974), Preparation and culture of neonatal mouse keratinocytes. Newborn NMRI mice of both sexes were killed by decapitation, the skin was dissected, washed in an antibiotic-antimycotic solution, and at 4°C, with the dermis side down, in Dispase II solution (1.2 U/ml in tissue culture medium M199+25mmol/l HEPES+15% fetal calf serum (FCS)+50U/ml penicillin/streptomycin (P/S) (specimen medium) at constant temperature overnight. Peel off the epidermis and pass Trypsin was used to prepare a single cell suspension. After centrifugation, the cell pellet was resuspended. After staining with naphthalene blue, the number of small spherical living cells was measured, and the cells were placed on a Primaria 24-well microtiter plate at 4×10 ⁵ Cells/cm ² density, inoculated on tissue culture medium (M199+15%FCS+50U/ml P/S), after constant temperature at 37°C for 24 hours, with phosphate-buffered saline (PBS) Wash the cells, and then insert in serum-free tissue culture medium (M199 + 50U/ml P/S + 0.5% ethanol) with the test substance and without the test substance for another 24 hours at 32.5°C. After that, add 0.4μci /50μl ³ H-methylthymidine (40ci/mmol). After 4 hours, aspirate the medium and add 500μl ice-cold 10% trichloroacetic acid (TCA) to end the reaction. Wash the cells with TCA and PBS, pass through in Incubate in proteinase K solution (10mmol/l Tris-HCl, 10mmol/l EDTA, 10mmol/l NaCl, 0.2% Triton-X100, pH8.0, 50μg/ml protein kinase K) to dissolve it, and centrifuge to dissolve it The product is clarified. The radioactivity in the supernatant is determined by scintillation photometry and the concentration of the DNA is determined by fluorometry after staining the DNA with a specific color with diamidinophenylindol (DAPI) .

Afterwards, calcitriol and compounds A and B had the following _IC50 values:

Calcitriol 2×10 ^-9 mol/l

Compound A 1×10 ^-8 mol/l

Compound B 3.2×10 ^-9 mol/l

Dosage prevents ³ H-thymidine from intercalating into DNA.

Calcitriol and the compound of the present invention, 26,27-ring-24a, 24b-two carbon-9,10-broken bile-5Z, 7E, 10(19), 23E-tetraene-1(S), 3( R), 24a(R)-triol (compound C) and 26, 27-cyclo-24a, 24b-bisadditional-9,10-sequence-5Z, 7E, 10(19), 23E-tetraene- There was virtually no difference in the differentiation-promoting effects of 1(S), 3(R), and 24a(S)-triol (compound D).

It is known from the literature (Mangelsdorf, D.J. et al., J. Cell Biol. 98: pp. 391-398 (1984)) that treatment of human leukemia cells (promyeloid lineage HL60) with calcitriol in vivo induces cell differentiation into macrophages.

For the purpose of quantifying the differentiation-stimulating effect of calcitriol analogs, the following tests were carried out:

HL60 cells were cultured in tissue culture medium (RPMI-10% fetal bovine serum) at 37°C in an air atmosphere containing 5% CO ₂ .

For the testing of the substances, the cells were separated by centrifugation and 2.8 x ¹⁰⁵ cells/ml were inoculated in tissue culture medium without phenol red. Dissolve the substance to be tested in ethanol and dilute to the desired concentration with tissue culture medium without phenol red. Mix the gradient dilution with the cell suspension at a ratio of 1:10, pipette 100 μl of the cell suspension containing the substance to be tested into the wells of a 96-well microtiter plate, and use a similar method for comparison. Add solvent to the cell suspension. After being kept at 37°C for more than 96 hours in an air containing 5% CO ₂ , add 100 μl of NBT-TPA solution [nitroblue tetrazolium (NBT), the final concentration in the solution is 1 mg/ml, myristyl phorbol meat Myristate (TPA), the final concentration in the solution is 2×10 ^-7 mol/l] pipetted into each well of the 96-well microtiter plate containing the cell suspension.

。By incubating for 2 hours at 37°C in an air atmosphere containing 5% CO ₂ , NBT was reduced to insoluble formazan in cells differentiated into macrophages due to the release of oxygen radicals in the cells, promoted by TPA.

.

To terminate the reaction, the contents of the 96-well microtiter plate were aspirated, methanol was added to fix the adhered cells, and after fixation they were dried.

结晶，向各凹坑中吸移100μl氢氧化钾（2val/l）及100μl二甲亚砜，并用超声波粉碎1分钟。甲

的浓度用分光光度法在650nm处进行测定。Intracellular formazan produced for lysis

To crystallize, pipette 100 μl of potassium hydroxide (2 val/l) and 100 μl of dimethyl sulfoxide into each pit, and ultrasonically disintegrate for 1 minute. First

The concentration was determined spectrophotometrically at 650nm.

，其浓度被视为HL60细胞分化诱导成巨噬细胞的量度，待试物质的相对效应可由ED₅₀（等试物质）/ED₅₀（钙三醇）的商数算得。The resulting armor

, its concentration is regarded as a measure of the induction of HL60 cell differentiation into macrophages, and the relative effect of the test substance can be calculated by the quotient of ED ₅₀ (equal test substance)/ED ₅₀ (calcitriol).

Therefore, the ED ₅₀ values of calcitriol, vitamin C and vitamin D are 1.8×10 ^-9 mol/l, 2.2×10 ^-9 mol/l and 2.5×10 ^-9 mol/l, respectively.

Due to the reduced risk of hypercalcemia, the substances according to the invention are particularly suitable for the preparation of medicines for the treatment of diseases characterized by hyperproliferation, such as hyperproliferative skin diseases (psoriasis) and malignant tumors (leukemia, colon cancer, breast cancer). The prerequisite for successful treatment is to first check the presence of calcitriol receptors in the target organ.

Therefore, the present invention also relates to pharmaceutical preparations, which contain at least one compound represented by general formula I together with a pharmaceutically acceptable carrier. The compounds of the invention can be prepared as solutions in pharmaceutically acceptable solvents. or made Emulsions, suspensions or dispersions in suitable pharmaceutically acceptable solvents or carriers, or in the form of pills, tablets or capsules with solid carrier substances known per se. For topical use, the compounds of the invention are conveniently formulated as a cream or ointment, or in a pharmaceutical form suitable for topical use. Each such dosage form may also contain other pharmaceutically acceptable and nontoxic adjuvants, such as stabilizers, antioxidants, binding agents, colorants, emulsifiers or flavoring agents. The compounds of this invention are suitably administered in the form of sterile solutions suitable for injection or intravenous infusion, or for oral administration via the alimentary canal, or as creams, ointments, lotions, or hard disks suitable for transdermal administration. It is used in the form of an ointment, as described in EP-A-0387077.

The daily dose is 0.1μg/patient/day-1000μg (1mg)/patient/day, preferably 1.0-500μg/patient/day.

In addition, the present invention also relates to the application of the compound represented by the general formula I in the preparation of medicine.

According to the present invention, the preparation of side chain homologous vitamin D derivatives shown in general formula I is carried out as follows: the compound of general formula IV

Wherein R ¹ ' is a hydrogen atom or a protected hydroxyl group;

^R2 ' is a hydroxyl protecting group, and

A, X and R ⁵ and R ⁶ have the meanings described in general formula I

When necessary, the double bond in the side chain is selectively hydrogenated to generate a compound of general formula IVa

In the formula, R ¹ ', R ² ', A, X and R ⁵ and R ⁶ have the meanings described in the general formula IV, and

If necessary, after the reduction of the carbonyl functional group, and if necessary, the reverse isomeric hydroxyl compound shown in the general formula IIIa and IIIb generated by the reaction is separated

In the formula, R ¹ , R ² , A, X and R ⁵ and R ⁶ have the meanings described in the general formula IV, and B and D have the meanings described in the general formula 1

Afterwards, irradiate with ultraviolet light to reverse the 5,6-double bond of the stereoisomer and convert it into a compound of general formula II

In the formula, R ¹ ', R ² ', A, B, D, X, and R ⁵ and R ⁶ have the meanings described in the general formula IIIa/IIIb

The compound is then converted to the compound of formula I by cleavage of the hydroxy protecting group present and, if necessary, partial or complete esterification of the hydroxy group.

The reduction of the pendant carbonyl function in the compound of formula IV is carried out, for example, with cerium trichloride/sodium borohydride in a polar solvent. The reduction produces either the R-hydroxy isomer, or the S-hydroxy isomer represented by general formulas IIIa and IIIb, respectively. The two isomers can be separated by chromatography.

If desired, double strands on the side chains can be selectively hydrogenated prior to reduction of the carbonyl function. Lithium-tri-tert-butoxyaluminum hydride, etc. Suitable for use as a hydrogenating agent in polar solvents.

The conversion of the compound of formula IIIa/IIIb to the compound of formula II is then carried out, for example, by irradiation with ultraviolet light in the presence of a so-called "triplett sensitizer". Within the scope of the invention, anthracene is used for this. The 5,6- double bond inversion.

Next, the hydroxyl protecting group present is removed. Preferably, under the conditions of using tetra-n-butylammonium fluoride, and when necessary, the free hydroxyl group is partially esterified with an appropriate carboxylic acid halide (halogen-chlorine, bromine) or carboxylic anhydride according to the usual method or complete esterification.

Raw material preparation

1.1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(S)-formyl-9,10-off-preg-5E,7E,10(19)-tri Alkene 1:

1 was prepared according to the method of MJ Calverley (Tetrahydron 43, p. 4609 (1987), see also International Patent Application WO 87/00834). Also described in above-mentioned document R ¹ is the preparation method of the original compound of hydrogen atom,

2.1(S), 3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9, 10-off-5E, 7E, 10(19)-tri En-21-carbaldehyde 2:

Aldehyde 2 was prepared by a new method.

a. At 25°C, add 15.57 g of ethyl diethylphosphoryl-ethoxyacetate ( Prepared according to W. Grell and H. Machleidt, "Liebigs Ann. Chem. 699, p. 53 (1966)) dissolved in 200 ml of THF. After the addition was complete, it was stirred at 60°C for another 90 minutes, recooled to 25°C, and a solution of 6.2 g in 70 ml of THF was added dropwise. After stirring under reflux for 2 hours, the cooled reaction solution was poured into water, and extracted with ethyl acetate. After drying ( _{Na2SO4 )} and concentration, the crude product was chromatographed on silica gel with hexane/ethyl acetate. The main fraction yielded 5.2gl(S), 3(R)-bis-(tert-butyldimethylsilyloxy)-23-(ethoxy-9,10-diaphragm-5E, 7E, 10(19 )-Ethyl tetraene-24-carboxylate, an oily mixture of isomers of the C-22 double bond.

b. Dissolve 5.2 g of the product obtained in a. in 120 ml of toluene, and slowly add 20 ml of 20% diisobutylaluminum hydride in toluene at 0°C. After 30 minutes, the reaction solution was carefully poured into NH ₄ Cl solution at 0°C and extracted with ethyl acetate. After routine treatment, 4.88gl(S), 3(R)-bis(tert-butyldimethylsilyloxy)-23-ethoxy-9,10-diaphragm-5E, 7E, 10(19 ), 22-tetraen-24-ol, a colorless oily mixture of isomers, was added to the following step without purification.

c. The compound obtained in b. (4.88 g) was stirred in a mixture consisting of 55 ml of dichloromethane and 55 ml of 70% aqueous acetic acid for 4 hours at room temperature. Next, NH ₃ solution was added, neutralized, and extracted with dichloromethane. The crude product was chromatographed on silica gel with hexane/ethyl acetate. According to this method, 2.02gl(S), 3(R)-bis-(tert-butyldimethylsilyloxy)-24-hydroxy-9,10-bromo-5E, 7E, 10(19 )-trien-23-one 5, as a colorless oil.

¹ H-NMR (CDCl ₃ ): δ=0.01ppm (s, 12H, Si-CH ₃ ), 0.52 (s, 3H, H-18), 0.81 and 0.84 (s, je 9H, Si-t-butyl) , 0.90 (d, J=7Hz, 3H, H-21), 3.09 (t, J=5Hz, 1H, OH), 4.10 (dd, 1H, H-24), 4.16 (m, 1H, H-3), 4.21 (dd, 1H, H-24), 4.39 (m, 1H, H-1), 4.88, 4.93 (s, je 1H, H-19), 5.77 6.39 (d, J=11Hz, je 1H, H- 6, H-7).

d. The product obtained in C. (2.02g) was dissolved in 25ml of methanol and 25ml of THF and 300mg of sodium borohydride was added at 0°C. After stirring at 0°C for 1.5 hours, the reaction mixture was poured into _NH4Cl solution and extracted with ethyl acetate. 1.75 g of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-9.10-sanchole-5E,7E,10(19)-triene-23,24- Diol 6, a 23-epimer mixture in the form of a colorless oil, was used as such in the following reaction.

e. 1.75g of the product obtained in d. was dissolved in 40ml of toluene, and 1.23g of lead tetraacetate was added in portions under ice-water cooling. After stirring for 30 minutes, 1.0 g of Pb(OAc) _₄ were added again and stirring was continued at +5 to +10°C for 15 minutes. For work-up, NaHCO ₃ solution was added, the resulting suspension was filtered through celite, and the filtrate was extracted with ethyl acetate. The crude product was chromatographed on silica gel with hexane/ethyl acetate. After crystallization of the main fraction from ethanol, 560 mg of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-off Pregnant-5E, 7E, 10(19)-triene-21-carbaldehyde, melting point 101-104°C.

Aldehyde 1 and aldehyde 2 are compared with the formula

The reaction of the indicated phosphorane produces the compound of general formula (IV) (Wittig reaction).

Preparation of the phosphorus ylide used:

1. Isobutylcarbonylmethylenetriphenylphosphorane

a. Bromomethyl. Isobutyl ketone

50 ml of isobutyl methyl ketone are dissolved in 240 ml of methanol, 20 ml of bromine are added at 0°C and, after the addition is complete, stirred for a further 1.5 hours at +10°C. Thereafter, 360 ml of water were added and stirring was continued for 16 hours at room temperature. For isolation, saturated common salt solution is added to the reaction mixture, the separated organic phase is separated, and the aqueous phase is extracted with diethyl ether. The pooled organic phases were washed with ₁₀ % _{Na2CO3 solution} and dried over _Na2SO4 . After filtration, the solvent was removed in a water jet pump vacuum and the residue was distilled. The main fraction contains 53.7g of bromomethyl and isobutyl ketone, whose K ^15-20 _P is 67-69°C.

b. Isobutylcarbonylmethyltriphenylphosphonium bromide.

In a 500 ml round bottom flask, bromomethyl isobutyl ketone (53.6 g) and triphenylphosphine (78.5 g) were uniformly mixed and kept at room temperature under nitrogen atmosphere for 12 hours after the initial intense reaction heat effect had decayed. Thereafter, the solid reactant was dissolved in 330 ml of dichloromethane and heated at reflux for 30 minutes. After adding 500 ml of ether, it was allowed to cool to room temperature and the product was isolated by filtration. After drying, 111.7 g of phosphonium salt were obtained, melting at 244-245°C.

c. Isobutylcarbonylmethylenetriphenylphosphorane

111.6 g of the product obtained in b. were mixed with 1500 ml of dichloromethane and 1500 ml of 2N NaOH and stirred at room temperature for 30 minutes. _The organic phase was separated, washed with water and dried over _Na2SO4 . The solid residue obtained after concentration was recrystallized from tert-butyl methyl ether to obtain 72.2 g of the ylide having a melting point of 120-121°C.

2. Isopentylcarbonylmethylenetriphenylphosphorane

The title compound was produced by bromination of isoamyl methyl ketone in a manner similar to that described in 1. The bromide reacts with triphenylphosphine to generate the phosphonium salt and 2N NaOH to generate the ylide.

Using 50.0ml of isoamyl methyl ketone and 18.2ml of bromine as raw materials, purified by distillation to obtain 54.68g of 1-bromo-5-methylhexan-2-one, K ^15-20 _P is 80-86°C. 54.58 g bromide and 74.14 g triphenylphosphine were used as starting materials. 91.6 g of phosphonium salt were obtained, melting at 230-233°C. Starting from 91.6 g of the phosphonium salt, after treatment with NaOH and recrystallization of the crude product from dichloromethane/ester, 69.8 g of the title compound were obtained, m.p. 64-67°C.

3. Isopropoxymethylcarbonylmethylenetriphenylphosphorane

2.43 g of sodium were dissolved in 150 ml of isopropanol. After adding 20.0 g of chloromethylcarbonylmethylenetriphenylphosphorane (R.F. Hudson et al., J. Org. Chem. 28 p. 2446 (1963)), it was dissolved in 200 ml of isopropanol and heated at reflux for 8 hours. The cooled reaction mixture was poured into common salt solution, and extracted with ethyl acetate. The oily residue obtained after concentration is chromatographed on silica gel with ethyl acetate. 9.53 g of the title compound were obtained, melting at 134°C.

4. (2-Isopropoxyethyl)-carbonylmethylenetriphenylphosphorane

a.1-Bromo-4-isopropoxy-butan-2-one

In a solution formed by dissolving 68.2g of 4-isopropoxy-2-butanone (FBHasan et al., J.Biolog.Chem.256, p. 7781, 1981) in 315ml of methanol, drop at 0°C 26.9 ml of bromine were added, followed by stirring at +10°C for 1.5 hours. Next, 470 ml of water was added dropwise to the reaction solution, followed by stirring at room temperature for 16 hours. For isolation, it was poured into saturated salt solution and extracted with ether. The crude product was distilled to obtain 78.07 g of the bromine derivative with a K ^15-20 _P of 95°C.

b. 4-Isopropoxy-2-oxo-butyl-triphenylphosphonium bromide

According to the method described in 1., 133.35 g of phosphonium salt were obtained from 78.0 g of the bromide obtained in a. and 97.85 g of triphenylphosphine, melting at 183°C.

c. (2-isopropoxyethyl)-carbonylmethylenetriphenylphosphorane

The phosphonium bromide obtained in b. (133.2 g) was treated with 2N NaOH in dichloromethane as described in 1. After recrystallization of the crude product from ethyl acetate, 64.38 g of the title compound were obtained, melting at 97°C.

5. (1-Ethylpropoxymethyl)-carbonylmethylenetriphenylphosphorane

Similar to the preparation method of isopropoxymethylcarbonylmethylene in triphenylphosphorane, the solution formed by dissolving 3.04g of sodium in 100ml of 3-pentanol was mixed with 25.0g of chloromethylcarbonylmethylenetriphenyl Phosphorane reaction gave the title compound as a crystalline oil, melting at 66-70°C.

6. Cyclopropylmethoxymethylcarbonylmethylenetriphenylphosphorane.

Similar to the preparation method of isopropoxymethylcarbonylmethylenetriphenylphosphorane, 5.58g sodium is dissolved in 25.0g cyclopropylmethanol and A solution made of 200ml of toluene was reacted with 30.0g of chloromethylcarbonylmethylenetriphenylphosphorane. The title compound was obtained as a solid, melting at 121°C.

7. (3-Butynyl)-carbonylmethylenetriphenylphosphorane

Dissolve 20.0g of methylcarbonylmethylenetriphenylphosphorane in 628ml of tetrahydrofuran, and add 41.3ml of butyllithium (1.6mol in hexane) dropwise at -78°C. Next, add 5.0ml of propargyl Bromine. After being heated to room temperature, the reaction mixture is placed on ice/salt solution and extracted with ethyl acetate. After drying the organic phase with sodium sulfate, 23.4 g of solids are obtained. Purify by column chromatography (silica gel/ethyl acetate ), yielding 15.4 g of the title compound, melting at 135-136°C.

8. (3-butenyl)-carbonylmethylenetriphenylphosphorane

From 15.0 g of methylcarbonylmethylene triphenylphosphorane dissolved in 471 ml of tetrahydrofuran, with 31.0 ml of butyllithium and 4.28 ml of allyl bromide, a reaction similar to 7 was carried out to obtain the title compound as a crystalline oil, dissolved in The point is 92-93°C.

By changing the ketone component used in the Wittig reaction, the compound shown in general formula IV can be prepared in a similar manner.

Example 1

1.6 g of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-offpreg-5E,7E,10(19) -Triene-21-carbaldehyde was dissolved in 50 ml of toluene, and the resulting solution was stirred at 80° C. for 16 hours under an argon atmosphere after addition of 3.02 g of isopentylcarbonylmethylenetriphenylphosphorane. The solvent is then removed under reduced pressure and the residue is chromatographed on silica gel with hexane/ethyl acetate. The main fraction yielded 1.15 g of [1(S), 3(R)-bis-(tert-butyldimethylsilyloxy)-9,10-diaphragm-5E, 7E, 10(19), 23(E )-tetraen-24-yl]-4-methyl-pentan-1-one as a colorless oil.

¹ H-NMR (CDCl ₃ ): δ=0.01ppm (s, 12H, Si-CH ₃ ), 0.56 (s, 3H, H-18), 0.87 (s, 18H, Si-t.-butyl); 0.88 (d, J=7Hz, 6H, C-(CH ₃ ) ₂ ), 0.95 (d, J=7Hz, 3H, H-21); 4.25 (m, 1H, H-3); 4.55 (m, 1H , H-1); 4.95 and 5.00 (s, je1H, H-19); 5.82 and 6.46 (d, J=11Hz, je1H, H-6, H-7); 6.10 (d, J=16Hz, 1H, H-24); 6.80 (m, 1H, H-23).

Example 2

572 mg of cerium trichloride heptahydrate were dissolved in 10 ml of methanol, and the compound prepared in Example 1 (1.10 g) dissolved in 5 ml of methanol was added. After adding 61 mg of sodium borohydride, it was stirred at 0° C. for 30 minutes. For separation, the reaction mixture was poured into water, extracted with dichloromethane, dried over _Na2SO4 , and _concentrated . The diastereoisomeric alcohol mixture thus obtained is chromatographed on silica gel using hexane/ethyl acetate. In the elution sequence, 290 mg of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-24-(1-hydroxy-4-methylpentyl)-9,10 - Severo-5E, 7E, 10(19), 23(E)-cholatetraene (epimer A) and 120 mg of epimer B. These two epimers exhibit identical NMR spectra.

¹ H-NMR (CDCl ₃ ): δ=0.01ppm (s, 12H, Si-CH ₃ ), 0.49 (s, 3H, H-18), 0.86 (s, 18H, Si-t.-butyl); 0.86 (d, J=7Hz, 6H, C-(CH ₃ ) ₂ ); 0.88 (d, J=7Hz, 3H, H-21); 4.16 (m, 1H, H-3); 4.48 (m, 1H, H-1); 4.88 and 4.93 (s, jelH, H-19); 5.40 (dd, J=15.5u.7Hz, 1H, H-24); 5.55 (m, 1H, H-23); 5.77 and 6.40 (d, J=11Hz, jelH, H-6, H-7).

Example 3

290 mg of the product obtained in Example 2 (epimer A) was dissolved in 80 ml of toluene, and the resulting solution was used in a Pyrex hard glass immersion reactor after adding 44 mg of anthracene and 0.01 ml of triethylamine. A high-pressure mercury lamp (Philips HPK125) was used for irradiation. The irradiation time was 3.5 minutes. A stream of nitrogen was introduced to ensure that the solution was evenly stirred. After concentration and chromatography on silica gel with hexane/ethyl acetate, 241 mg l(S),3(R)-bis-(tert-butyldimethylsilyloxy)-24-(1-hydroxy-4 -Methylpentyl)-9,10-Sanchole-5Z,7E,10(19),23(E)-tetraene as a colorless oil. [α] ²⁰ _D +49.6° (CHCl ₃ , C=0.425).

120 mg of the polar isomer (epimer B) prepared in Example 2 was treated in a similar manner to obtain 113 mg of a colorless oil. [α] ²⁰ _D +41.4° (CHCl ₃ , c=0.285).

Example 4

225 mg of the product obtained from epimer A according to Example 3 was dissolved in 5 ml of THF, and the resulting solution was stirred at 60°C for 60 minutes after adding 1.31 ml of 1M tetrabutylaluminum fluoride THF solution. After cooling, it was poured into a saturated salt solution, and extracted with ethyl acetate. The crude product was chromatographed on silica gel with hexane/ethyl acetate and yielded 85 mg of 24-(1-hydroxy-4-methylpentyl)-9,10-sanchole-5Z,7E,10(19), 23E-tetraene-1(S),3(R)-diol, white foam.

¹ H-NMR (CDCl ₃ ): δ = 0.57ppm (s, 3H, H-18), 0.84 (d, J = 7Hz, 3H, H-21); 0.92 (d, J = 7Hz), 6H, C -( _CH3 ) ₂ ; 4.03 (m, 1H, H-25); 4.23 (m, 1H, H-3); 4.43 (m, 1H, H-1); 5.00 and 5.33 (s, jelH, H- 19), 5.45 (dd, J=15.5u, 7Hz, 1H, H-24); 5.60 (m, 1H, H-23); 6.02 and 6.38 (d, J=1Hz, jel1H, H-6, H- 7).

The product (95 mg) obtained with epimer B as in Example 3 was treated in a similar manner to give 35 mg of the epimer triol as a colorless oil. The NMR spectra of the two epimers are identical.

Example 5

In a manner similar to that described in Example 1, 2.05 g of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20-(R)- Methyl-9,10-depren-5E,7E,10(19)-triene-21carbaldehyde was reacted with 3.4 g of isobutylcarbonylmethylenetriphenylphosphorane. After chromatographic purification, [1(S), 3(R)-bis-(tert-butyldimethylsilyloxy)-9,10-bromo-5E, 7E, 10(19), 23( E)-tetraen-24-yl]-3-methyl-butan-1-one, m.p. 79-81°C (prepared from ethanol), [α] ²⁰ _D +52.6° (CHCl ₃ , c= 0.500).

Example 6

The product obtained in 1.75g of Example 5 was reduced under the conditions of Example 2 to obtain the epimer oily mixture 1 (S), 3 (R)-bis-(tert-butyl Dimethylsilyloxy)-24-(1(R,S)-hydroxy-3-methylbutyl)-9,10-sanchole-5E,7E,10(19),23E-tetraene. After chromatographic separation on silica gel with hexane/ethyl acetate, 780 mg of epimer A and 600 mg of epimer B were obtained in elution order as colorless oils with no difference in NMR spectra.

Example 7

Carry out triple sensitized photoisomerization similarly to Example 3, and then carry out silyl ether (silylether) decomposition similarly to Example 4, in this way from 700 mg of epimer A prepared according to Example 6, to prepare 240mg of 24-(1-hydroxy-3-methylbutyl)9,10-sanchole-5Z,7E,10(19),23E-tetraene-1(S),3(R)-diol (compound A), the decomposition temperature range is 119-125°C. [α] ²⁰ _D +38.8° (methanol, c=0.505).

330 mg of epimer B were treated in a similar manner to give 129 mg of 24-(1-hydroxy-3-methylbutyl)-9,10-sanchole-5Z,7H,10(19),23E-tetraene-1 (S), 3(S)-diol (compound B), decomposition temperature range 139-145°C, [α] ²⁰ _D + 54.8° (methanol, c=0.505).

Example 8

170 mg of the product obtained in Example 5 was dissolved in 5 ml of THF, and the resulting solution was stirred at room temperature for 90 minutes after adding 200 mg of lithium-tri-tert-butoxyaluminum hydride. For isolation, 0.8 ml of saturated NH ₄ Cl solution was added, filtered, and the filtrate was concentrated and the crude product was chromatographed on Al ₂ O ₃ (Merck, neutral, step III) to give 108 mg of 1-[1(S),3( R)-bis-(tert-butyldimethylsilyloxy) 9,10-decanol-5E,7E,10(19)-trien-24-yl]-3-methyl-but-1- Ketone, a colorless oil.

¹ H-NMR (CDCl ₃ ): δ=0.53ppm (s, 3H, H-18); 4.22 (m, 1H, H-3); 4.54 (m, 1H, H-1); 4.93 und 4.98 (m , je1H, H-19); 5.82 und 6.46 (d, J = 11Hz, je1H, H-6, H-7).

Example 9

Carry out photochemical double bond isomerization similarly to Example 3, and carry out silyl ether decomposition similarly to Example 4, and use 100 mg of the product obtained in Example 8 to obtain 50 mg of 1-[1(S), 3(R) -Dihydroxy-9,10-diol-5Z,7E,10(19)-trien-24yl]-3-methyl-butan-1-one.

Ultraviolet (methanol): 212nm (ε=14 300), 265 (15 860).

Example 10

1.6g 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-off-5E,7E,10(19)- Triene-21-carbaldehyde and (2-isopropoxyethyl)-carbonylmethylenetriphenylphosphorane were reacted similarly to Example 1 to obtain 1.15 g of 1-[1(S), 3(R) -Bis-(tert-butyldimethylsilyloxy)-9,10-san-5E,7E,10(19),23(E)-tetraen-24-yl]-3-isopropoxy yl-propan-1-one as a colorless oil.

¹ H-NMR (CDCl ₃ ): δ=0.01ppm (s, 12H, Si-CH ₃ ), 0.55 (s, 3H, H-18), 0.86 and 0.90 (s, je9H, Si-t.-butyl ); 0.96 (d, J = 7Hz, 3H, H-21); 1.15 (d, J = 7Hz, 6H, C (CH ₃ ) ₂ ); 3.60 (m, 1H, CH-O); 3.73 (t, J = 7Hz, 2H, CH2 _- O); 4.23 (m, 1H, H-3); 4.55 (m, 1H, H-1); 4.95 and 5.00 (m, je1H, H-19); 5.83 and 6.46 (d, J=11Hz, je1H, H-6, H-7); 6.11 (d, J=15.5Hz, 1H, H-24), 6.87 (m, 1H, H-23).

Example 11

With the method similar to Example 2, the photoisomerization similar to Example 3, and the silyl ether decomposition similar to Example 4, by 1.05g of the product prepared in Example 10, 143mg24-( 1(R,S)-Hydroxy-3-isopropoxypropyl) -9,10-Chole-5Z, 7E, 10(19), 23-tetraene-1(S), 3(R)-diol, a 1:1 mixture of diastereomers, available under high pressure separated by liquid chromatography. The NMR spectra of the two isomers are identical.

¹ H-NMR (CDCl ₃ ): δ = 0.57ppm (s, 3H, H-18), 0.94 (d, J = 7Hz, 3H, H-21); 1.15 (d, J = 7Hz6H, C ( _CH3 ) ₂ ), 4.17 (m, 1H, H-3); 4.21 (m, 1H, H-25); 4.38 (m, 1H, H-1), 4.98 and 5.29 (m, jelH, H-19); 5.45 (dd, J=15.5 and 7Hz, 1H, H-24); 5.63 (m, 1H, H-23); 6.02 und 6.38 (d, J=11Hz, jelH, H-6, H-7).

Example 12

Using aldehyde 1 and isopropoxymethylcarbonylmethylenetriphenylphosphorane as raw materials, the isomer B (5Z, 7E, 22E-1 (S) was prepared in a procedure similar to that of Examples 1-4 , 3(R), 24(S)-9,10-off-24a,24b-bisaddition-24b-oxochol-5,7,10(19),22-tetraene-1,3,24- Triol), melting point is 131-132°C.

Example 13

Using aldehyde 1 and (2-isopropoxyethyl)-carbonylmethylenetriphenylphosphorane as raw materials, the isomer B (5Z, 7E, 22E -1(S), 3(R), 24(S) -9, 10-off-24a, 24b, 24c-triadditional carbon-24c-oxachol-5, 7, 10(19), 22-four Alkene-1,3,24-triol with a melting point of 125-126°C.

Example 14

Similar to Example 1, 0.85 g of 1(S), 3(R)-bis-(tert-butyldimethylsilyloxy)-20(R)-methyl-9,10-off-5E, 7E, 10(19)-triene-21-carbaldehyde was reacted with 4.5 g of cyclopropylmethylcarbonyltriphenylphosphorane. Chromatography on silica gel with hexane/ethyl acetate gave 500 mg of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-26,27-cyclo-24a,24b -Diadditional carbon-9, 10-choline-5E, 7E, 10(19), 23E-tetraen-24a-one as a colorless foam.

¹ H-NMR (CDCl ₃ ): δ=0.01ppm (s, 12H, Si-CH ₃ ); 0.09 and 0.50 (m, each of 2H, H-26 and H-27); 0.50 (s, 3H, H- 18); 0.83 and 0.85 (s, each 9H, Si-t. butyl); 0.91 (d, J=7.3Hz, 3H, H-21); 0.96 (m, 1H, H-25); 2.47 (d , J=6Hz, 2H, H-24b); 4.16 (m, 1H, H-3); 4.47 (m, 1H, H-1); 4.89 and 4.93 (s, each 1H, H-19); 5.77 and 6.40 (d, J=11Hz, each 1H, H-6 and H-7); 6.08 (d, J=15.5Hz, H-24); 6.75 (ddd, J=15.5, 9, 6.5Hz, 1H, H -twenty three).

Example 15

Similar to Example 2, the product prepared in Example 14 was reacted to give 200 mg of 1(S),3(R)-bis-(tert-butyldimethylsilyloxy)-26,27-cyclo-24a , 24b-bisaddition carbon-9, 10-broken bile-5E, 7E, 10 (19), 23E-tetraen-24a (R, S)-alcohol, an oily mixture of epimers, both NMR spectra were indistinguishable.

¹ H-NMR (CDCl ₃ ): δ = 0.01ppm (s, 12H, Si-CH ₃ ); 0.09 and 0.40 (m, respectively 2H, H-26 and H-27); 0.50 (s, 3H, H -18); 0.68 (m, 1H, H-25); 0.81 and 0.86 (s, each 9H, Si-t.-butyl); 0.88 (d, J=7Hz, 3H, H-21); 1.40 ( t, J=7Hz, H-24b); 4.13 (m, 1H, H-24a); 4.17 (m, 1H, H-3); 4.49 (m, 1H, H-1); 4.88 and 4.93 (s, Each is 1H, H-19); 5.45 (dd, J=15.5, 6.5Hz, 1H, H-24); 5.59 (ddd, J=15.5, 7, 6.5Hz, 1H, H-23); 5.77 and 6.40 (d, J = 11 Hz, each of 1H, H-6 and H-7).

Example 16

Similar to Example 3, after carrying out triple-sensitized photoisomerization and deprotection similar to Example 4, using 190 mg of the compound described in Example 15 as a starting material, 86 mg of 26,27-ring- 24a, 24b-bisadditional carbon-9, 10-diabolite-5Z, 7E, 10(19), 23E-tetraene-1(S), 3(R), 24a(R,S)-triol, for A 1:1 mixture of diastereomers can be separated by high pressure liquid chromatography. The NMR spectra of the two diastereomers are identical.

¹ H-NMR (CDCl ₃ ): δ=0.09 and 0.49 (m, 2H, H-26 and H-27 respectively); 0.53 (s, 3H, H-18); 0.70 (m, 1H, H-25 );0.93(d,J=7Hz,3H,H-21);4.18(m,1H,H-24a);4.22(m,1H,H-3);4.43(m,1H,H-1); 5.00 and 5.32 (s, each 1H, H-19); 5.50 (dd, J=15.5, 6.5Hz, H-24); 5.64 (ddd, J=15.5, 7, 6.5Hz, 1H, H-23) ; 6.02 and 6.38 (d, J=11Hz, 1H, H-6 and H-7 each).

Example 17

Using aldehyde 1 and (1-ethylpropoxymethyl)-carbonylmethylenetriphenylphosphorane as raw materials, the isomer B (5Z, 7E, 22E-1(S), 3(R), 24(S)-26, 27-Dimethyl-24a, 24b,-bisaddition-24b-oxa-9, 10-bromo-5, 7, 10(19), 22- tetraene-1,3,24-triol) with a melting point of 103-105°C.

Example 18

Using aldehyde 1 and cyclopropylmethoxymethylcarbonylmethylenetriphenylphosphorane as raw materials, according to the procedure similar to that of Example 1-4, isomer B (5Z, 7E, 22E-1 ( S), 3(R), 24(S)-26, 27-Cyclo-24a, 24b, 24c-triaddoc-24b-oxa-9, 10-bromo-5, 7, 10(19), 22-tetraene-1,3,24-triol).

¹ H-NMR (DMSO-d ₆ ): δ = 0.16ppm (m, 2H); 0.43 (m, 2H); 0.53 (s, 3H); 1.00 (d, J = 6Hz, 3H); 3.21 (m, 4H);4.00(m,2H);4.19(m,1H);4.51(d,J=5Hz,1H);4.70(d,J=5Hz,1H);4.75(m,1H);4.82(d, J = 5Hz, 1H); 5.21 (m, 1H); 5.39 (m, 2H); 5.98 (d, J = 11Hz, 1H); 6.18 (d, J = 11Hz, 1H).

Example 19

Using aldehyde 1 and (3-butynyl)-carbonylmethylene triphenylphosphorane as raw materials, the isomer B (5Z, 7E, 22E-1 (S ), 3(R), 24(S)-24-(3-butynyl)-9, 10-sequence-5, 7, 10(19), 22-tetraene-1, 3, 24-tri Alcohol) with a melting point of 115-118°C.

Example 20

Using aldehyde 1 and (3-butenyl)-carbonylmethylenetriphenylphosphorane as raw materials, according to procedures similar to those of Examples 1-4, isomer B (5Z, 7E, 22E-1 ( S), 3(R), 24(S)-24-(3-butenyl)-9,10-sanchole-5,7,10(19),22-tetraene-1,3,24- Triol), melting point is 146-147°C.

Claims (9)

1. Preparation of side chain homologous vitamin D derivatives represented by general formula I

In the formula, R ¹ represents a hydrogen atom or a hydroxyl group, ^R2 represents a hydrogen atom, ^R3 or ^R4 represents a hydroxyl group and the other substituent represents a hydrogen atom, or ^R3 and ^R4 together represent an oxygen atom, R ⁵ and R ⁶ each represent a linear or branched chain alkyl group containing up to 4 carbon atoms, or together represent a 3, 4, 5 or 6-membered saturated carbocyclic ring formed with a tertiary carbon atom, B and D either each represent a hydrogen atom; or together represent a second bond (double bond in E configuration), and A represents a direct bond between carbon atoms 20 and 22, while X represents an alkyleneoxy-(CH ₂ ) _n O-, where n=1 to 3, or when A represents a direct bond and B and D together represent a second bond,

The method is characterized in that the compound of the general formula IV is converted into the compound of the general formula IVa after selective hydrogenation of the double bond on the side chain if necessary

In the formula R ¹ is a hydrogen atom or a protected hydroxyl group, R ² is a hydroxyl protecting group, while A, X and R ⁵ and R ⁶ have the meanings described in general formula I,

Wherein R ¹ , R ² , A, X and R ⁵ and R ⁶ have the meanings described in the general formula IV, and if necessary, after the reduction of the carbonyl-free functional group, and if necessary, the general formula generated by the separation reaction Mixture of epimeric hydroxy compounds of formulas IIIa and IIIb

wherein R ¹ , R ² , A, X and R ⁵ and R ⁶ have the meanings described in general formula IV, while B and D have the meanings described in general formula I, By irradiating with ultraviolet light, the stereoisomer is reversed at the 5,6-double bond and converted into the compound shown in the general formula II

In the formula, R ¹ , R ² , A, B, D, X and R ⁵ and R ⁶ have the meanings described in the general formulas IIIa and IIIb, The compound of formula II is then converted to the compound of formula I by removal of the hydroxy protecting group present and, if necessary, by partial or complete esterification of the hydroxy group. 2. The method of claim 1, wherein ^R1 represents a hydroxyl group. 3. The method of claim 1, wherein ^R2 represents a hydrogen atom. 4. The method of claim 1, wherein B and D together are a second bond. 5. The method of claim 1, wherein ^R3 or ^R4 represents a hydroxyl group. 6. The method of claim 1, wherein n in X is 1 or 2. 7. The method of claim 1, wherein ^R5 and ^R6 represent methyl. 8. The method of claim 1, wherein R ⁵ , R ⁶ and the tertiary carbon atom together represent a cyclopropyl ring. 9. The method of claim 1, wherein the compound obtained is: 24-(1(R)-Hydroxy-4-methylpentyl)-9,10-sanchole-5Z,7E,10(19),23E-tetraene-1(S),3(R)-di alcohol, 24-(1(S)-Hydroxy-4-methylpentyl)-9,10-sanchole-5Z,7E,10(19),23E-tetraene-1(S),3(R)-di alcohol, 24-(1(R)-Hydroxy-4-methylbutyl)-9,10-sanchole-5Z,7E,10(19),23E-tetraene-1(S),3(R)-di alcohol, 24-(1(S)-Hydroxy-4-methylbutyl)-9,10-sanchole-5Z,7E,10(19),23E-tetraene-1(S),3(R)-di alcohol, 24-(1(R)-Hydroxy-4-methylbutyl)-9,10-sanchole-5Z,7E,10(19)-triene-1(S),3(R)-diol, 24-(1(S)-Hydroxy-4-methylbutyl)-9,10-sanchole-5Z,7E,10(19)-triene-1(S),3(R)-diol, 24-(1(R)-Hydroxy-4-isopropoxypropyl)-9,10-Sanchole-5Z,7E,10(19),23E-Tetraene-1(S),3(R) -diol, 24-(1(S)-Hydroxy-3-isopropoxypropyl)-9,10-Sanchole-5Z,7E,10(19),23E-Tetraene-1(S),3(R) -diol, 24-Isopropoxymethyl-9,10-Sanchole-5Z, 7E, 10(19), 22E-tetraen-1(S), 3(R), 24(R)-triol, 24-Isopropoxymethyl-9,10-Sanchole-5Z, 7E, 10(19), 22E-tetraen-1(S), 3(R), 24(S)-triol, 24-(2-Isopropoxyethyl)-9, 10-sanchole-5Z, 7E, 10(19), 22E-tetraene-1(S), 3(R), 24(R)-tri alcohol, 24-(2-Isopropoxyethyl)-9, 10-sanchole-5Z, 7E, 10(19), 22E-tetraene-1(S), 3(R), 24(S)-tri alcohol, - Triols, - Triols,